Background: This proposal asks for continued support of leDEA-SA, a large collaborative network of HIV care and antiretroviral treatment (ART) programs in Southern Africa. Aims: (i) to provide the best available data on long-term program effectiveness in children, adolescents and adults; (ii) to describe long-term regimen durability and tolerability and examine different monitoring and treatment strategies, with a focus on viral load and second-line ART; (iii) to describe co-morbidities, focusing on tuberculosis and cancer and (iv) to follow up pregnant women on ART and cohorts of ART-exposed non HIV-infected infants and infected infants, and (v) to build capacity in the region. Methods: 20 urban and rural ART programs from 7 countries (Botswana, Lesotho, Malawi, Mozambique, Republic of South Africa, Zambia, Zimbabwe) with follow-up up to 10 years will pool data to create a database of 400,000 HIV-infected adults, 10,000 adolescents, 36,000 children and 6,700 infants, with about 70% of patients on ART. In South Africa, HIV data will be linked to the National Cancer Registry, National Death and Birth Registers, and the Tuberculosis Register. Mortality, loss to follow-up, tuberculosis and recurrent tuberculosis, and AIDS-defining and other cancers will be analyzed, as well as fertility, CD4 cell trajectories, treatment-limiting toxicities, response to second-line ART and resistance mutations in adults and children failing ART. Trends in exposure to antenatal and postnatal ARVs, pregnancy outcomes including prematurity and anthropometry, feeding practices and growth over 18 months will be examined in sub- cohorts of pregnant women and infants. We will survey the provision of care to cancer patients, and compare different screening strategies for invasive cervical cancer. Statistical analyses will consider the hierarchical nature of the data, missing data and loss to follow-up, competing risks and time-dependent confounding, and new methods will be developed. Accumulating results will be used to build and parameterize a mathematical model of ART in children, adolescents and adults, which will reflect the realities of HIV care and ART in Southern Africa, and inform health policy. RELEVANCE: Southern Africa is the region most heavily affected by the HIV epidemic. Since 2004, efforts by governments and others have resulted in a massive increase in HIV/AIDS interventions and particularly ART. Operational, clinical and public health research is urgently needed to guide the long-term delivery of HIV care and ART to the many patients in need, including pregnant women, infants, children and adolescents.